Inhibitory kappa B kinases as targets for pharmacological regulation

Abstract

The inhibitory kappa B kinases (IKKs) are well recognized as key regulators of the nuclear factor kappa B (NF-kB) cascade and as such represent a point of convergence for many extracellular agents that activate this pathway. The IKKs generally serve to transduce pro-inflammatory and growth stimulating signals that contribute to major cellular processes but also play a key role in the pathogenesis of a number of human diseases. Therefore, the catalytic IKKs represent attractive targets for intervention with small molecule kinase inhibitors. IKK isoforms are assembled as variable multi-subunit IKK complexes that regulate not only NF-kB dimers, but also protein substrates out-with this cascade. Consequently, close consideration of how these individual complexes transduce extracellular signals and more importantly what impact small molecule inhibitors of the IKKs have on functional outcomes are demanded. A number of adenosine triphosphate (ATP)-competitive IKKb-selective inhibitors have been developed but have demonstrated a lack of activity against IKKa. A number of these chemicals have also exhibited detrimental outcomes such as cellular toxicity and immuno-suppression. The impact of small molecule inhibitors of IKK catalytic activity will therefore be reappraised, examining the advantages and potential disadvantages to this type of intervention strategy in the treatment of diseases such as arthritis, intestinal inflammation and cancer. Furthermore, we will outline some emerging strategies, particularly the disruption of protein-protein interactions within the IKK complex, as an alternative route towards the development of novel pharmacological agents. Whether these alternatives may negate the limitations of ATP-competitive molecules and potentially avoid the issues of toxicity will be discussed.

Peptide-based inhibition of IκB kinase/nuclear factor-κB pathway protects against diabetes-associated nephropathy and atherosclerosis in a mouse model of type 1 diabetes

“…Remarkably, NBD peptide reversed the cellular responses induced by long-term exposure to HG, but did not influence either NF-κB or cell viability under normoglycaemic conditions. Hence, the primary role of NF-κB in normal cellular functions is preserved, resulting in less toxicity, which represents an advance over other NF-κB inhibitors [18,19,35]. Our results constitute the first in vivo characterisation of the nephroprotective effect of NBD peptide.…”

“…c-Rel, NF-κB1 and NEMO) further implicate NF-κB in diabetes [30][31][32]. Moreover, anti-inflammatory compounds exhibit an ameliorating effect on diabetic symptoms and long-term complications by directly inhibiting IKK activity [33,34], although limitations due to cellular toxicity and immunosuppression have prompted a search for alternative strategies [19]. Our results in an experimental model of combined hyperglycaemia and hyperlipidaemia (diabetic Apoe −/− mice) demonstrate that NF-κB activation status in kidney and aorta highly correlates with the severity of nephropathy and atherosclerosis, thus confirming the key role of the NF-κB inflammatory pathway in the pathogenesis of diabetic complications.…”

“…Although several NF-κB inhibitors have reached phase II/III clinical trials for inflammatory diseases [18,19], most research into cardiovascular or renal diseases is only in the preliminary experimental phase [20]. This work investigates whether IKK-targeted NF-κB inhibition improves diabetic complications.…”

A Novel Inhibitor of I-KappaB Kinase Beta Ameliorates Experimental Arthritis through Downregulation of Proinflammatory Cytokines in Arthritic Joints

“…The role of IKKβ in inflammatory diseases has been demonstrated in multiple disease-relevant cells and animal models using selective IKKβ inhibitors. [20][21][22][23]49) However, the mechanisms of the action of IKKβ inhibitors are complicated because NF-κB plays an important role in immune response, inflammation, cell differentiation, proliferation and survival in various cells and tissues. [8][9][10] An IKKβ inhibitor could induce a variety of functional alterations in various cells through suppression of the NF-κB signaling as contribution to the efficacy or otherwise side effects, in addition to inhibiting proinflammatory cytokine productions in arthritic joints.…”

EcSTAT3ic about K63-Linked Ubiquitylation of IKKβ

“…Very few of these inhibitors have reached clinical trials, all of them ATP-competitive IKKb selective inhibitors that exhibit off-target/side effects such as cellular toxicity and immunosuppression. 7 As such, there is a need for novel strategies to target and inhibit aberrant IKKb activity. By inhibiting the catalytic activity of the Ubc13/ Uev1A E2 enzyme, this paper demonstrates that pharmacological blockage of IKKb K63-linked ubiquitylation might be a valid approach to inhibiting STAT3 activation in vivo.…”